title: Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor.
abstract: The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline derivative(designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C]KD2 was obtained in 99% radiochemical purity.Moderate blood–brain barrier (BBB) passage was predicted for KD2 from an in vitro transport assay with P-glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiography of rat and mouse spleen slices demonstrated that [11C]KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C]KD2 was observed in dynamic positron emission tomography(PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiography study with post-mortem spinal cord slices from amyotrophic lateral sclerosis (ALS)patients with [11C]KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C]KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C]KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2.
authors.affiliation: Department of Nuclear Medicine, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: Daniel
authors.initials: D
authors.lastname: Bieri
authors.forename: Roger
authors.initials: R
authors.lastname: Slavik
authors.forename: Konstantin
authors.initials: K
authors.lastname: Drandarov
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller
authors.forename: Stjepko
authors.initials: S
authors.lastname: Cermak
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis*; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D009025:Morpholines / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects*
chemical_list: C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; D018435:ATP Binding Cassette Transporter, Subfamily B; D001798:Blood Proteins; D007202:Indicators and Reagents; D007211:Indoles; D009025:Morpholines; D019275:Radiopharmaceuticals; D043885:Receptor, Cannabinoid, CB2
keywords: autoradiography; cannabinoid receptor type 2 ligand; neurodegeneration; radiolabeling; small-animal PET